Arthur Weiss, M.D., Ph.D.
Chief of Rheumatology
Ephraim P. Engleman Distinguished Professor
Chief, Division of Rheumatology, Parnassus
Director, Medical Scientist Training Program
Investigator, Howard Hughes Medical Institute
University of California, San Francisco
513 Parnassus Avenue, Room S-1032
San Francisco, CA. 94143-0795
Dr. Weiss received his Ph.D. (Immunology, 1978) and M.D. (1979) degrees from the University of Chicago. He did a postdoctoral fellowship at the Swiss Institute for Experimental Cancer Research in Lausanne, Switzerland. Dr. Weiss completed his training in internal medicine and rheumatology at UCSF. In 1985, he joined the faculty of the Division of Rheumatology and the Howard Hughes Medical Institute at the University of California, San Francisco. His major academic activities include directing his research laboratory as well as serving as Chief of the Division of Rheumatology and as Director of the Medical Scientist Training Program. Dr. Weiss is a member of the National Academy of Sciences, Institute of Medicine and the American Academy of Arts and Sciences.
Many rheumatologic diseases result from the abnormal activity of the immune system. In order to understand the mechanisms responsible for the abnormal activity of lymphocytes of the immune system, the normal mechanisms responsible for regulating their functions must be understood. The Weiss lab is interested in the biochemical signal transduction mechanisms that control T and B cell responses. The response to antigen by lymphocytes involves complex molecular interactions involving multiple receptors.
Cell Surface Molecules and Molecular Events Involved in T Lymphocyte Activation The response of T lymphocytes to antigen on an antigen-presenting cell represents a unique opportunity to study how complex molecular interactions between cells can initiate signal transduction events leading to cell differentiation. The focus of my lab has been to understand how T cell surface molecules initiate signal transduction events that regulate T cel1 responses. The T cell antigen receptor is a complex eight chain oligomeric structure representing the products of six genes. Only two of the chains, alpha and betta, are required to recognize antigen. The other chains, zeta as well as CD3 gamma, delta and epsilon, are involved in coupling the receptor to cytoplasmic protein tyrosine kineses (PIKs). We have identified a common sequence motif in the cytoplasmic domains of the CD3 and zeta chains which interact with cytoplasmic ErIKs. Biochemical studies as well as genetic evidence suggest that two distinct classes of PIKs, members of the Src and Syk/ZAP-70 families, interact with the receptor. In fact, we showed that mutations in ZAP-70 represent the molecular basis for a rare human severe combined immunodeficiency (SCID) syndrome. Current efforts are aimed at understanding the regulation of these kineses and at identifying their substrates. One of the downstream substrates of the TCR-regulated PTKs is the protooncogene Vav. Mice deficient in Vav have an impairment in T and B cell development as well as a defect in antigen receptor signal transduction. The function of Vav has not been clear. However, our recent studies suggest that it functions in a proximal position within the TCR signaling pathway. Studies are ongoing to define the specific molecular mechanism of Vav function. CD45, transmembrane protein tyrosine phosphatase expressed only on hematopoietic cells, regulates T cell antigen receptor signaling by influencing the activity of cytoplasmic PIKs of the Src family. We showed that dimerization of CD45 negatively regulates its phosphatase function. We would like to identify CD45 ligands and understand how phosphatase function is regulated by ligand. In an effort to do so, we have collaborated with Robert Fletterick in the Department of Biochemistry to solve the crystal structure of CD45. T cells can not be activated by antigen receptor stimulation alone. Other signals involving interactions between molecules on an antigen presenting cell and T cell are required. CD28, a T cell transmembrane protein that binds to the B7 molecule expressed on B cells and macrophages, initiates an unidentified signaling event which activates a transcriptional factor involved in regulating lymphokine gene expression. We are interested in identifying the events involved in CD28 signaling and their relative importance in T cell differentiation/ activation.